Angiogenesis is a process for formation of a systemic vascular network initiating from embryonic stage, and is related to generation via complex processes including not only proliferation of vascular endothelial cells but also migration of endothelial cells or tube formation, formation of basement membrane, etc.
Recently, studies on factors regulating angiogenesis have been progressed, and therapeutic application thereof has been attempted. Development of tumors and the like profoundly relates to dysregulated angiogenesis. Treatment thereof requires suppression of angiogenesis, however, on the contrary, therapy for promoting angiogenesis has also been required widely.
For example, factors for promoting angiogenesis, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFBF), hepatocyte growth factor (HGF), and the like have been found, and by utilizing these growth factors and genes thereof, therapeutic methods for the diseases essentially requiring improvement of blood circulation, such as arteriosclerosis obliterans, ischemic heart disease, and the like, have been attempted and examined.
However, since these growth factors are proteins, there are many problems such as difficulty with the oral administration, an anaphylactic reaction caused by repeated administration, safety of virus in case of gene therapy using a viral vector and adverse side reactions like edematous, and accordingly new development of therapeutic agents are desired.
Physiological angiogenesis is recognized in microvascular formation of mature tissues and is known to be generated by such a physical factor as change in intravascular pressure. It has been reported, for example, that long-term administration of prazosin or adenosine having vasodilating activity increases physical shear stress to blood vessels in microcirculation and thus promotes angiogenesis (Dawson, J. M., Cardiovasc. Res. 23, 913-920, 1989; and Ziada, A. M., Cardiovasc. Res. 18, 724-732, 1984), however, these compounds have no direct angiogenesis promoting action.